In 1983, the etiological cause of AIDS was determined to be the human immunodeficiency virus (HIV). In 1985, it was reported that the synthetic nucleoside 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT) inhibits the replication of human immunodeficiency virus. Since then, a number of other synthetic nucleosides, including 2xe2x80x2,3xe2x80x2-dideoxyinosine (DDI), 2xe2x80x2,3xe2x80x2-dideoxycytidine (DDC), and 2xe2x80x2,3xe2x80x2-dideoxy-2xe2x80x2,3xe2x80x2-didehydrothymidine (D4T), have been proven to be effective against HIV. After cellular phosphorylation to the 5xe2x80x2-triphosphate by cellular kinases, these synthetic nucleosides are incorporated into a growing strand of viral DNA, causing chain termination due to the absence of the 3xe2x80x2-hydroxyl group. They can also inhibit the viral enzyme reverse transcriptase.
The success of various synthetic nucleosides in inhibiting the replication of HIV in vivo or in vitro has led a number of researchers to design and test nucleosides that substitute a heteroatom for the carbon atom at the 3xe2x80x2-position of the nucleoside. European Patent Application Publication No. 0 337 713 and U.S. Pat. No. 5,041,449, assigned to BioChem Pharma, Inc., disclose racemic 2-substituted-4-substituted-1,3-dioxolanes that exhibit antiviral activity. U.S. Pat. No. 5,047,407 and European Patent Application No. 0 382 526, also assigned to BioChem Pharma, Inc., disclose that a number of racemic 2-substituted-5-substituted-1,3-oxathiolane nucleosides have antiviral activity, and specifically report that the racemic mixture of 2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (referred to below as BCH-189) has approximately the same activity against HIV as AZT, with little toxicity. The (xe2x88x92)-enantiomer of the racemate BCH-189, known as 3TC, which is covered by U.S. Pat. No. 5,539,116 to Liotta et al., is currently sold for the treatment of HIV in combination with AZT in humans in the U.S.
It has also been disclosed that cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (xe2x80x9cFTCxe2x80x9d) has potent HIV activity. Schinazi, et al., xe2x80x9cSelective Inhibition of Human Immunodeficiency Viruses by Racemates and Enantiomers of cis-5-Fluoro-1-[2-(Hydroxymethyl)-1,3-Oxathiolane-5-yl]Cytosinexe2x80x9d Antimicrobial Agents and Chemotherapy, November 1992, pp. 2423-2431. See also U.S. Pat. No. 5,210,085; WO 91/11186, and WO 92/14743.
Another compound that exhibits efficacy against HIV both in vitro and in vivo is 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil, which is also known as MKC-442. 
MKC-442 is described, for example, in U.S. Pat. No. 5,461,060.
MKC-442, although a nucleoside analogue, functions as a non-nucleoside reverse transcriptase inhibitor. It is considered an allosteric inhibitor because it appears to exert its activity by binding to an xe2x80x9callosteric positionxe2x80x9d, i.e., one other than the binding site, of the enzyme. Preclinical tests suggest that MKC-442 may possess characteristics that address several of the therapeutic challenges of HIV. When tested in cell culture assay systems against wild-type (drug-sensitive) and several mutant strains of HIV known to be resistant to established non-nucleoside reverse transcriptase inhibitors, MKC-442 retained much of its ability to inhibit HIV replication. In these studies, MKC-442 displayed greater potency than nevirapine against wild-type and mutant strains of HIV. Preclinical studies of MKC-442 in two drug combinations with AZT or with DDI and in three drug combinations with AZT and saquinavir have demonstrated synergistic inhibition of HIV replication.
Studies in animals suggest a favorable safety and pharmacokinetic profile for MKC-442. Animal pharmacokinetic analyses showed good oral bioavailability and excellent penetration into the central nervous system, a significant site of HIV replication that is poorly penetrated by many currently marketed anti-HIV drugs. In rats, for example, the concentration of MKC-442 in the brain was 100% of that seen in the plasma.
A Phase I study evaluated the pharmacokinetics and tolerance of single escalating doses of MKC-442 in HIV-infected volunteers. The compound was generally well tolerated, with only a few participants experiencing minor adverse effects at the higher dose levels. In the groups receiving higher doses, concentrations of the drug in the plasma reached levels mich higher than the levels required to suppress 90% of the virus in culture.
Preliminary data from a Phase I/II double-blind, placebo controlled trial designed to evaluate the safety and efficacy of repeated multiple oral doses of MKC-442 in HIV-infected patients has now also been evaluated. A total of 49 patients were treated with MKC-442 for up to two months. Doses ranging from 100 mg to 1000 mg twice a day were given to groups of six to eight patients at each dosage level. At the highest doses tested (705 mg and 1000 mg twice a day), the viral load was reduced by an average of 96% in all patients after one week. This reduction was mostly sustained at two weeks whereafter it was followed by a gradual increase in viral load from the nadir toward baseline levels. A single point mutation at position 13 of the reverse transcriptase that may be associated with resistance was found in the virus obtained from some patients. In over 308 patient-weeks of drug exposure, MKC-442 was well tolerated.
It is known that over a period of time, agents such as MKC-442 that are active against HIV induce mutations in the virus which reduce the efficacy of the drug. There is a need to improve the durability of antiviral efficacy produced by antiretroviral drugs, including MKC-442, by decreasing the rate at which such mutations arise. Further, although MKC-442 exhibits a favorable pharmacokinetic and biodistribution profile, there is always a desire to improve these parameters. There is also a need to decrease the metabolism of the drug, which can lead to an increase in the plasma concentration of or exposure to MKC-442.
U.S. Pat. No. 5,604,209, issued on Feb. 18, 1997 to Ubasawa et al., and assigned to Mitsubishi Chemical Corporation, discloses that certain 6-benzyl-1-ethoxymethyl-5-substituted uracil derivatives, including MKC-442, and certain 2xe2x80x2,3xe2x80x2-dideoxyribonucleosides, including 2xe2x80x2,3xe2x80x2-dideoxyinosine (DDI), 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT), AZT triphosphate, and 2xe2x80x2,3xe2x80x2-dideoxycytidine (DDC), exhibit a synergistic effect against HIV.
Japanese Patent Application No. 9-18384 filed on Jan. 31, 1997, by Mitsubishi Chemical Corporation, discloses a method for the treatment of HIV that includes the administration of a 6-benzyl-1-ethoxymethyl-5-substituted uracil derivative, including MKC-442, in combination with two or more nucleoside-type reverse transcriptase inhibitors or their esters, and in particular, those selected from the group consisting of AZT, 2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-thiacytidine (3TC), PMEA (9-(2-phosphonylmethoxyethyl) adenine (Gilead); PMPA: (R)-9-(2-phosphonyl-methoxypropyl)adenine); 1592U89 succinate ((1S,4R)-4-[2-amino-6-cyclopropyl-amino)-9H-purin-9-yl]-2-cyclopentene-1-methanol succinate); 2xe2x80x2,3xe2x80x2-dideoxyinosine (DDI); and 2xe2x80x2,3xe2x80x2-dideoxy-2xe2x80x2,3xe2x80x2-didehydrothymidine (D4T), and esters thereof.
In light of the strong activity of MKC-442 against HIV, it is an object of the present invention to provide a method and composition that includes MKC-442 for the treatment of patients infected with HIV that exhibits advantageous or improved pharmacokinetic, biodistribution, metabolic, resistance or other parameters over administration of MKC-442 alone.
It is also an object of the invention to improve the efficacy of MKC-442 during short periods of administration and over extended time periods.
It is yet another object of the present invention to provide a method and composition for the treatment of patients infected with HIV in which MKC-442 is administered in combination or alternation with a second compound that acts synergistically with MKC-442 against the virus.
It is still another object of the present invention to provide a method and composition for the treatment of patients infected with HIV in which MKC-442 is administered in combination or alternation with a second compound (or at least one other compound) that acts synergistically with MKC-442 against the virus.
It has been discovered that MKC-442 can be administered in combination with one or more antiviral agents to achieve an advantageous therapeutic effect against HIV. In some cases, the enhanced therapeutic effect is not attainable by administration of either agent alone. In a preferred but not necessary embodiment, the effect of administration of the two agents in combination or alternation is synergistic.
In one preferred embodiment, MKC-442 is administered in combination with a protease inhibitor. In particular embodiments, MKC-442 is administered in combination or alternation with either indinavir, nelfinavir ([3S-[2(2S*,3S*),3-alpha,4-a-beta,8a-beta-]]-N-(1,1-dimethylethyl)decahydro-2-)2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-3-isoquinolincarboxamide mono-methanesulfonatc), saquinavir, or amprenavir (141 W94) (S)-tetrahydrofuran-3-yl-N-[(1S,2R)-3-[N-[(4-aminophenyl)-sulfonyl]-N-isobutylamino]-1-benzyl-2-hydroxypropyl]carbamate.
In another preferred embodiment, MKC-442 is administered in combination or alternation with a nucleoside analog such as abacavir (1592U89) which is (1S,4R)-4-[2-amino-6-cyclopropyl-amino)-9H-purin-9-yl]-2-cyclopentene-1-methanol succinate, 3TC, or FTC.
In another embodiment, MKC-442 is administered in combination with a non-nucleoside reverse transcriptase inhibitor, such as DMP-266 (efavirenz; (S)-6-chloro-4-(cyclopropylethynyl)-1, 4-dihydro-4-(trifluoromethyl)-2H-3, 1-benzoxazin-2-one), delavirdine (1-[3-(1-methyl-ethyl)amino]-2-pyridinyl-4-[[5-[(methylsulfonyl)amino]-1H-indol-2-yl]carbonyl]-, monoethanesulfonate), or nevirapine.
In general, during alternation therapy, an effective dosage of each agent is administered serially, whereas in combination therapy, an effective dosage of two or more agents are administered together. The dosages will depend on such factors as absorption, biodistribution, metabolism and excretion rates for each drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Examples of suitable dosage ranges for protcase inhibitors, including for example, nelfinavir and indinavir, can be found in the scientific literature and in the Physicians Desk Reference. Many examples of suitable dosage ranges for other compounds described herein are found in public literature or can be determined easily using known methods. These dosage ranges can be modified as desired to achieve a desired result.
The disclosed combination and alternation regiments are useful in the prevention and treatment of HIV infections and other related conditions such as AIDS-related complex (ARC), persistent generalized lymphadenopathy (PGL), AIDS-related neurological conditions, anti-HIV antibody positive and HIV-positive conditions, Kaposi""s sarcoma, thrombocytopenia purpurea and opportunistic infections. In addition, these compounds or formulations can be used prophylactically to prevent or retard the progression of clinical illness in individuals who are anti-HIV antibody or HIV-antigen positive or who have been exposed to HIV.